What is the appropriate diagnostic and treatment approach for a 55-year-old male with severe anemia, macrocytic anemia, and increased iron stores?

Severe Normocytic Anemia with Iron Overload: Sideroblastic Anemia Workup Required

This 55-year-old male with severe anemia (Hb 6.4 g/dL), normal MCV (92 fL), normal reticulocyte count, and paradoxically elevated iron stores (increased serum iron, ferritin, and transferrin saturation) most likely has a sideroblastic anemia or bone marrow disorder requiring immediate bone marrow examination with iron staining to identify ring sideroblasts. 1

Critical Diagnostic Features

This presentation is highly atypical and concerning:

• Severe anemia with Hb 6.4 g/dL in an adult male is well below the WHO threshold of 13.0 g/dL and requires urgent evaluation 1
• Normal MCV (92 fL) with iron overload excludes typical iron deficiency anemia and suggests a defect in iron utilization rather than iron availability 1
• Normal reticulocyte count despite severe anemia indicates inappropriate bone marrow response and inability to compensate, pointing to deficiencies causing inappropriate erythropoiesis or primary bone marrow disease 1
• Elevated iron parameters (ferritin, transferrin saturation, serum iron) in the setting of anemia is paradoxical and characteristic of sideroblastic anemias where iron cannot be properly incorporated into hemoglobin 1

Immediate Diagnostic Algorithm

Step 1: Bone Marrow Examination (Urgent)

• Bone marrow aspirate and biopsy with Prussian blue iron staining is mandatory to identify ring sideroblasts (pathognomonic for sideroblastic anemia) and evaluate for myelodysplastic syndrome 1
• Ring sideroblasts are erythroblasts with iron-loaded mitochondria forming a ring around the nucleus, visible on iron staining 1

Step 2: Extended Laboratory Workup

• Measure serum copper and ceruloplasmin to evaluate for aceruloplasminemia, which presents with anemia, iron loading, and neurological symptoms 1
• Check lactate dehydrogenase (LDH) and haptoglobin to definitively exclude hemolysis, though normal reticulocyte count makes this unlikely 1
• Obtain peripheral blood smear to look for dysplastic features, basophilic stippling, or other morphological abnormalities 1
• Measure red cell distribution width (RDW) which may be elevated in sideroblastic anemia 1

Step 3: Trial of Pyridoxine (Vitamin B6)

• Initiate pharmacologic doses of pyridoxine 50-200 mg daily as X-linked sideroblastic anemia (XLSA) due to ALAS2 defects may be pyridoxine-responsive 1
• This can be started empirically while awaiting bone marrow results, as it is safe and may provide diagnostic and therapeutic benefit 1
• Monitor hemoglobin response over 4-8 weeks; if responsive, continue lifelong maintenance at 10-100 mg daily to avoid neurotoxicity from excessive doses 1

Step 4: Genetic Testing if Sideroblastic Anemia Confirmed

• ALAS2 gene sequencing for X-linked sideroblastic anemia (most common hereditary form) 1
• Consider testing for GLRX5, SLC25A38, and other rare causes if ALAS2 is negative and clinical suspicion remains high 1
• Ceruloplasmin (CP) gene testing if aceruloplasminemia suspected (very low ceruloplasmin with systemic iron loading) 1

Important Differential Diagnoses to Exclude

Myelodysplastic Syndrome (MDS)

• MDS with ring sideroblasts can present identically to hereditary sideroblastic anemia, especially in a 55-year-old male 1
• Bone marrow examination will differentiate: MDS shows dysplasia in multiple cell lines and may have cytogenetic abnormalities 1
• If MDS is confirmed, hematology referral is mandatory for risk stratification and consideration of disease-modifying therapy 1

Acquired Causes of Sideroblastic Anemia

• Review medication history for drugs causing sideroblastic anemia: isoniazid, chloramphenicol, linezolid, alcohol 1, 2
• Assess for lead toxicity if occupational exposure exists (though this typically causes microcytosis) 1
• Evaluate for copper deficiency which can cause sideroblastic changes, though this usually presents with neurological symptoms 1

Critical Management Considerations

Avoid Iron Supplementation

• Do NOT give oral or intravenous iron therapy as this patient already has iron overload and additional iron will worsen toxicity 1
• Iron supplementation is contraindicated in sideroblastic anemia where the problem is iron utilization, not availability 1

Monitor for Iron Overload Complications

• Check liver function tests and consider liver imaging as iron overload can cause hepatic fibrosis and hepatocellular carcinoma 1
• Screen for diabetes mellitus as pancreatic iron deposition can cause insulin-dependent diabetes 1
• Assess cardiac function if iron overload is severe, as cardiac siderosis can occur 1

Transfusion Strategy

• With Hb 6.4 g/dL, assess for symptoms of severe anemia (dyspnea, chest pain, altered mental status, hemodynamic instability) 3
• Consider red blood cell transfusion if symptomatic to achieve hemodynamic stability while diagnostic workup proceeds 3
• If chronic transfusions become necessary, initiate iron chelation therapy to prevent further iron accumulation 1

Treatment Based on Etiology

If hereditary sideroblastic anemia confirmed:

• Continue pyridoxine if responsive (50-200 mg daily initially, then 10-100 mg maintenance) 1
• Treat iron overload with phlebotomy if tolerated (preferred method) or chelation therapy if anemia precludes phlebotomy 1
• Monitor ferritin levels; target <500 mg/L to avoid toxicity, especially in younger patients 1

If MDS with ring sideroblasts:

• Hematology management with consideration of erythropoiesis-stimulating agents, lenalidomide, or hypomethylating agents depending on risk stratification 1
• Transfusion support with chelation as needed 1

If acquired/reversible cause identified:

• Discontinue offending medication 1, 2
• Treat underlying condition (e.g., alcohol cessation, copper supplementation) 1, 2

Common Pitfalls to Avoid

• Do not assume iron deficiency based on anemia alone—the elevated iron parameters completely exclude this diagnosis 1
• Do not delay bone marrow examination—this is the definitive diagnostic test and cannot be replaced by peripheral blood testing alone 1
• Do not give iron supplementation empirically—this will cause harm in sideroblastic anemia 1
• Do not miss MDS—in a 55-year-old, acquired MDS is more likely than hereditary sideroblastic anemia and requires different management 1
• Do not forget family screening if hereditary cause confirmed—XLSA has X-linked inheritance requiring evaluation of male relatives and female carriers 1

Hematology Referral

Immediate hematology consultation is mandatory given the severity of anemia, paradoxical iron overload, and likelihood of bone marrow pathology requiring subspecialty expertise 1